Introduction

There was a striking rise in mucormycosis cases during the second wave of covid-19 pandemic in India [1]. Mucormycosis (also called zygomycosis) is a serious fungal infection caused by a group of molds called mucoromycetes which includes Rhizopus spp., Mucor spp., Rhizomucor spp., Syncephalastrum spp., Cunninghamella, bertholletia, Apophysomyces spp., and Lichtheimia (formerly Absidia) spp. The Rhizopus oryzae is the most common type and responsible for nearly 60% of mucormycosis and accounts for 90% of the Rhino-orbital-cerebral mucormycosis (ROCM) [2]. It affects the paranasal sinuses and causing erosion of the orbital contents and can extend into skull base mucor. The multiplication of Mucor spores is favoured by numerous factors such as hypoxia, hyperglycaemic states, metabolic acidosis, diabetic ketoacidosis, increased free iron levels and decreased oxidative and non-oxidative fungicidal mechanism of leukocytes due to immunosuppression that leads to the catastrophic scenario of rhino orbital mucormycosis coinfection with covid-19 [3]. Rhino Orbital cerebral mucormycosis can be categorized as Possible, Probable, and Proven. A patient who shows clinical features in the background setting of recently (< 6 weeks) or concurrently treated COVID-19, diabetes mellitus, use of systemic corticosteroids and tocilizumab, mechanical ventilation, or supplemental oxygen is considered as Possible ROCM. When those clinical symptoms are supported by diagnostic nasal endoscopy findings, or contrast-enhanced MRI or CT scan, the patient is considered as Probable ROCM. Clinico-radiological findings with microbiological confirmation on direct microscopy or culture or histopathology with special stains or molecular diagnostics are vital to categorize a patient as Proven ROCM [4]. Mucormycosis is a life-threatening disease warrants early suspicion of diagnosis and extension by nasal endoscopy and radiological investigations, timely intervention of otolaryngologist by endoscopic surgical debridement along with concurrent intravenous antifungal agents is very crucial to control the original precipitating cause to reduce morbidity and mortality effectively. In this study, we have summarized the clinical manifestations, distribution of various stages, risk factors, diagnosis and management of rhino orbital cerebral mucormycosis associated with covid-19.

Methodology

A cross-sectional descriptive study on all post covid patients with microbiological or histopathological proven mucormycosis patients in mucormycosis special ward at Govt Stanley medical college Chennai a tertiary care centre during the period from May to October 2021 were included in the study.

The purpose of this study is to highlight the distribution of various stages based on clinical profile, contributing risk factors, disease course and outcome of Rhino orbital cerebral mucormycosis.

Patient detailed history including demographic data like Age, gender and socio-economic status were recorded. Past history of covid, duration of hospital stay, oxygen dependent status and steroid intake were noted. Underlying risk factors like Diabetes mellitus and other immunocompromised status were noted then complete Ear, Nose, throat, Ophthalmic, Neurological and Dental Examinations were carried out. Patients were Classified based on the proposed staging of Rhino-orbital-cerebral-Mucormycosis based on the location and extension of the disease, computerized tomography (CT) scan of the orbit, paranasal sinuses, and lung were utilised for all patients as the primary mode of imaging study, contrast-enhanced magnetic resonance imaging (MRI) of the orbits, brain and paranasal sinuses was also done for patients based on their disease course. All patients underwent endoscopic evaluation and nasal swabs taken followed by sent for KOH mount, fungal culture and histopathological examination (Figs. 1, 2). patient who satisfied inclusion criteria were recorded after obtaining detailed written and informed consent for their clinical and biological data regarding research purposes.

Fig. 1
figure 1

a Obtuse angled hyphae in KOH mount, b Computerised tomography showing left orbital and optic nerve involvement

Fig. 2
figure 2

a Stage-III Rhino orbital cerebral Mucormycosis, b Zero degree Endoscopic view of eschar over middle turbinate

Optimal management of mucormycosis requires multidisciplinary team efforts by various sectors. Owing to its high mortality, even the slightest clinical suspicion should warrant initiation of antifungal therapy and surgical line of management is planned according to the nasal endoscopic and diagnostic evaluation of CT which reveals the involvement of paranasal sinus.

Antifungal therapy includes injection Liposomal Amphotericin B given in all patients at a dose of 3–5 mg/kg diluted in 100 ml of 5% dextrose given slowly over 3 h with serial monitoring of renal function and serum electrolyte. Daily blood glucose monitored Injection regular insulin was also started. Amphotericin is started empirically as soon as possible once there is a clinical, radiological and endoscopic feature of mucormycosis. Surgical line of management is planned according to the extent of disease. Based on the diagnostic evaluation by endoscopy and CT, patients can be divided into 2 groups. (1) endoscopic surgical debridement (2) Endoscopic sinus surgery with medial orbital decompression (3) Revision Debridement with partial or total maxillectomy according to the maxillofacial involvement.

In this study 243 patients were evaluated into possible, probable and proven ROCM based on the clinical features, radiological findings with microbiological and histopathological evidence as well as recent laboratory covid 19 RTPCR report to discuss their perspectives in clinical presentation, risk factors, management and outcome.

Results

Demography

Median age of patients was 51 years with range from 28 to 75 years and 62.5% were males with M:F ratio 1.6 and predominantly from low socio-economic status. The median interval time between onset of COVID-19 and first symptoms of mucormycosis was twenty days (15–35). As they belong to the working age group in our society, deterioration due to this illness makes them the dependent population. As the case load increases, which also reflects badly on the economy of our country (Table 1).

Table 1 Age and demographic distribution

Clinical Features of ROCM

Out of 243 study population more than 73% of the rhino orbital cerebral mucormycosis patients had facial pain and swelling; next to it were headache and nasal stuffiness (53%). Nearly 64% patients had periorbital tenderness with significant lid oedema on examination. Other ophthalmic symptoms were loss of vision, proptosis, ptosis, chemosis and double vision (Fig. 3).

Fig. 3
figure 3

Clinical features of rhino orbital cerebral mucormycosis

Risk Factors

Among 243 study population, 45.8% (111) patients had received intravenous steroids during covid-19 management, 65% (158) were having diabetes and 30% (72) of them developed Diabetic Ketoacidosis. In this study 30% (72) patients were having new onset diabetes detected during their COVID-19 illness. Excessive and unmonitored use of steroids is a risk factor for mucormycosis in COVID-19. 45.8% of patients who had received steroids for COVID-19 disease presented with post-COVID mucormycosis symptoms. This excessive use of systemic steroids itself contributes to the increased blood sugar level. Nearly, 136 (55%) need prolonged nasal oxygen support three of them were under mechanical ventilator support during covid management. 132 (54%) patients had received Antivirals and immunomodulators (Table 2).

Table 2 showing incidence of various risk factors

Site of Involvement

Based on clinical features, imaging and intraoperative endoscopic findings rhino orbital cerebral mucormycosis were categorised into following stages among which Sino-nasal mucormycosis (Stage-II) was the most frequent form of mucormycosis as evidenced in 111 (46%) of COVID-19 patients followed by stage-I involving nasal cavity alone in 87 (36%) patients. Sino-orbital mucormycosis (Stage-III) noticed in 37 (15%) patients and finally, Rhino orbital cerebral (Stage-IV) involvement in 8 (3%) patients (Fig. 4). Four patients had pulmonary mucormycosis in association with ROCM. The most common form of paranasal sinus involvement was pansinusitis. In 162 (67%) cases, mucormycosis was extended to skull base spaces and pterygopalatine fossa involvement. Cavernous sinus involvement, developed in seven cases (46%). Clinical, radiological, and histological features of a patient with post covid ROCM were categorised with endoscopic findings was shown in (Table 3).

Fig. 4
figure 4

Distribution of ROCM based on involvement

Table 3 categorise the Rhino orbital cerebral mucormycosis Stages based on their clinical, radiological and histopathological findings

Management and Outcome

All of the patients were treated with intravenous amphotericin B liposomal (IV 5 mg/kg daily for 3 weeks) and maintenance under oral Posaconazole meanwhile patients with orbital involvement were managed with Trans Retroorbital Amphotericin B injection. Antifungal combination therapy was significantly associated with better outcome (p = 0.003). fourteen patients (5.7%) succumbed with stage- IV shows increased mortality as the result of extensive involvement (Fig. 5). All patients underwent surgical endoscopic debridement including 7 (29%) orbital decompression, except one patient who had severe lung involvement caused by COVID-19 (Fig. 6). Among which 91 patients need revision debridement which includes 34 (37.5%) orbital exenteration, 7 (8%) palatal debridement and 11 (12.6%) total maxillectomy (Table 4).

Fig. 5
figure 5

Outcome of various stages of post covid ROCM

Fig. 6
figure 6

a postoperative Endoscopic debridement of sinonasal mucormycosis, b Histopathology shows mucormycosis

Table 4 Showing frequency of Management of Mucormycosis

Discussion

In this cross-sectional study on post covid crisis of Rhino orbital cerebral mucormycosis with primary aim to focus on the clinical and demographical profile of the disease, risk factors, management and outcomes of Rhino orbital cerebral Mucormycosis.

The age and demographic profile of the patients we treated are mostly from middle aged and elderly persons with predominantly among males. Incidence of mucormycosis among females is decreased pointed out the possibility of estrogen in preventing fungal infection [2].

Honavar et al. in their study proposed the staging system of ROCM from the point of entry (nasal mucosa) on to the paranasal sinuses, orbit and brain, and severity in each of these anatomical locations based on disease progression. Our study followed the similar staging and observed that stage III & IV results in more mortality and morbidity [4].

Misra et al. in their study showed there is a positive association between COVID-19 and hyperglycaemic state with new onset diabetes in those who diagnosed with COVID-19. The interesting observation is that these patients had more severe hyperglycaemia which is proportional to the severity of COVID-19 infection various factors leading to this condition includes increased release of inflammatory mediators leading to cytokine storm, excessive steroid use, and virus mediated pancreatic beta-cell damage.

Direct virus mediated beta cell damage is caused by direct attachment of virus to the ACE receptors of pancreatic beta cell which lead to beta cell destruction and lead to the development of insulin dependent diabetes mellitus. Insulin dependent diabetes usually presents with hyperglycemic states with diabetic ketoacidosis.

Another mechanism is triggering of beta-cell autoimmunity by virus which produces antibody against pancreatic beta-cell antigens. The etiopathogenesis of type 1 diabetes associated with other viral infections like mumps, cytomegalovirus rubella virus is due to the release of antigens from the damaged pancreatic beta cells into the systemic circulation leads to the activation of T lymphocytes which is the causative factor for the development of autoimmunity and further pancreatic damage [5].

Severe systemic inflammatory response triggered by COVID-19 infection produce an increased stress to our immune system which further worsens the glycemic status. SARS-CoV-2 infection triggers the release of hyperglycemic hormones like glucocorticoids leading to uncontrolled blood glucose levels in diabetic patients, severe COVID-19 lead to disseminated activation of the immune system which causes release of pro-inflammatory cytokines such as Interleukin-6 (IL-6) and Tumor Necrosis Factor (TNF) alpha, both of which are known to induce insulin resistance and hyperglycemia [6]

In this study we found a statistically significant correlation between the diabetes and development of diabetic ketoacidosis with a p value of 0.01 in patients with COVID-19 infection both in pre diabetic and new onset cases of diabetes [7]. In the case of new onset diabetes among 72 patients, 68 cases developed diabetic ketoacidosis. This shows a trend towards insulin dependent Diabetes Mellitus (Type 1 DM). In the case of known case of type 2 DM more than 50% developed DKA. This positive correlation denoted that mucormycosis is an opportunistic fulminant infection which occurs in patients with uncontrolled diabetes mellitus and diabetic ketoacidosis. Hyperglycemic states increase the expression of GRP78 which acts as an endothelial receptor for Mucor fungus. Acidotic state which occurs with hyperglycemic states, leads to deterioration of cellular immunity. In normal individuals iron is found in the bound state with transferring and ferritin. In acidic pH the ability of iron binding decreases which lead to increased availability of serum free iron to the fungi. Fungal hypha produces a substance called rhizoferrin, which has higher affinity for iron. This iron-rhizoferrin complex is then taken up by the fungus through siderophores or iron permease for its important metabolic functions which increase the invasiveness of the fungi. Phycomycetes can grow fast and can destroy the sinuses within a day. There is impairment of chemotactic and phagocytic activity in Diabetic keto acidosis [8, 9]

Injury to the epithelium in upper airway of covid 19, paved the way for fungus to invade tissues [10]. The plenty misuse use of steroids in the symptomatic management of COVID-19 increase the risk of Rhino orbital cerebral mucormycosis [11]. The indiscriminate use of steroids even in mild COVID-19 infection provides a ‘fertile soil ‘for the development of mucormycosis in an already diabetic patient. Along with the adverse effect of steroid induced hyperglycemia corticosteroids inhibits the migration, ingestion and phagolysosome fusion of macrophages. A total dose of methyl prednisolone of 2–7 g can be a predisposing factor for the development of mucormycosis [12]. In diabetics even a short duration of steroid therapy can lead to mucormycosis [13]. In ECCM study it has been found that 46% of patient who developed mucormycosis had history of steroid usage one month before and 44% had received immunosuppressant's [14]. The use of steroids in the treatment of COVID-19 infection must be under judicious monitoring and to be started only after proper triage of the patients.

Coexisting COVID-19 severity, multiple comorbidities, poor general condition of the patients makes it a difficult scenario in terms of anesthesia complications. Surgical protocol for endoscopic debridement based on involvement of paranasal sinus, erosion of orbital content and invasion of skull base. In surgical treatment, due to the different patterns of spread and extension of the disease, a general surgical protocol cannot be adapted in the case of mucormycosis. Each of the cases has to be planned individually and at some instance has to be modified intraoperatively makes it a challenging situation for the operating surgeon. This is one of the major challenges faced by otolaryngologists in the surgical debridement. Surgical modalities vary from mere sinus debridement to extensive debridement up to infratemporal and temporal fossa. In complicated cases destructive procedures like orbital exenteration and maxillectomy has to be considered. In our study population we have got a good recovery in 72% patients with post operative diagnostic nasal endoscopy showing based on the post-operative follow-up is by weekly diagnostic nasal endoscopic examination and planned accordingly. Only 26% required revision debridement based on our study.

Conclusion

From this study, we conclude that covid be the predisposing factor for Rhino-orbito-cerebral mucormycosis especially in patients with diabetes with increased usage of steroids and immunomodulators. Treatment needs multimodality combined approach with antifungals and surgical endoscopic debridement with surveillance. Early diagnosis, prompt surgical and medical management with proper management of co morbidities will help to overcome these challenges and provides a satisfactory outcome.